Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma.
Although a number of effective therapies are available for localized prostate cancer, metastatic prostate cancer is difficult to treat and impossible to cure. Identification of the gene products that enable a prostatic carcinoma cell to metastasize should facilitate an understanding of the processes leading to metastasis. To characterize the contribution of matrix metalloproteinase-9 (MMP-9, gelatinase B or the 92-kd type IV gelatinase/collagenase) to the development of metastasis in prostate cancer, we reduced MMP-9 expression in metastatic murine prostatic carcinoma cells using a ribozyme. The ribozyme transfected cells had lower basal levels of MMP-9 as well as decreased levels after stimulation by transforming growth factor-beta or phorbol 12-myristate 13-acetate when compared with the parental cells or with control transfectants. The cells with down-regulated MMP-9 were unable to form lung colonies in the experimental metastasis assay, whereas the controls and parental cells readily formed metastases. All cell types readily formed tumors after injection and down-regulation of MMP-9 did not adversely affect the rate of tumor growth. Thus, MMP-9 expression is required for hematogenous metastasis in a murine prostate model system raising the possibility that it may play an equivalent role in human prostate cancer.
Sehgal
G
G
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Hua
J
J
Bernhard
E J
EJ
Sehgal
I
I
Thompson
T C
TC
Muschel
R J
RJ
D000818:Animals; D002277:Carcinoma / Q000378:metabolism* / Q000556:secondary*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016337:RNA, Catalytic / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016337:RNA, Catalytic; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017364:Collagenases; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate